Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior
Aberrant hippocampal Atp8a1 levels are associated with altered synaptic strength, electrical activity, and autistic-like behavior
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DOI：
10.1016/j.bbadis.2016.06.005
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发表时间：
2016-09-01
影响因子：
6.2
通讯作者：
Banerjee, Probal
中科院分区：
文献类型：
--
作者：
Kerr, Daniel J.;Marsillo, Alexandra;Banerjee, Probal
IV型ATPase是推测的氨基磷脂转位酶(APLT)，通常被称为Flppase。与年龄匹配的对照组相比，在来自河马校园和青少年自闭症受试者颞叶的死后组织匀浆中观察到明显的翻转酶Atp8a1的诱导。为了模拟人类的数据，在出生后第6天(P6)的早期发育阶段，将表达Atp8a1的重组慢病毒注射到C57BL/6小鼠的海马区，使其发育。经慢病毒-Atp8a1处理的成年小鼠(Atp8a1+)的透射电子显微镜分析显示，与注射空病毒的小鼠相比，海马CA1区的兴奋性突触更少、更弱。在20ms刺激间隔的双脉冲记录(PPR)中，Atp8a1+小鼠的Schaffer侧支通路受到显著抑制。在三个房间的社交测试中，Atp8a1+的小鼠没有表现出比新物体更喜欢被包裹的陌生人鼠标的偏好，这是一种典型的自闭症样行为。与此形成鲜明对比的是，Atp8al(-/-)小鼠表现出对陌生鼠标的偏好，而不是新奇物体，这是小鼠典型的神经行为特征。然而，与Atp8a1+小鼠类似，Atp8a1(-/-)小鼠在CM中的兴奋性突触比野生型对照小鼠更少和更弱，而在PPR中则在20ms刺激间期表现出抑制。这些发现表明，在发育早期，Atp8a1水平的升高和降低都对大脑连接有害，但只有Atp8a1的升高与异常的社会行为有关。因此，Atp8a1水平升高的小鼠可能成为自闭症研究的潜在模型。(C)2016爱思唯尔B.V.保留所有权利。
Type IV ATPases are putative aminophospholipid translocases (APLTs), more commonly known as flippases. A pronounced induction of the flippase Atp8a1 was observed in post-mortem tissue homogenates from the hippo campus and temporal lobe of juvenile autistic subjects compared to age-matched controls. In order to simulate the human data, C57BL/6 mice were allowed to develop after intra-hippocampal injection of recombinant lentivirus expressing Atp8a1 at the early developmental stage of postnatal day 6 (P6). Transmission electron microscopy (TEM) analysis of the lentivirus-Atp8a1 treated (Atp8a1 +) mice in adulthood revealed fewer and weaker excitatory synapses in the hippocampal CA1 region compared to mice injected with empty virus. Significant inhibition of the Schaffer collateral pathway was observed in the Atp8a1 + mice in paired-pulse recording (PPR) at 20-ms inter-stimulus interval. In the three-chambered sociability test, the Atp8a1 + mice displayed no preference for an encaged stranger mouse over a novel object, which is a characteristic autistic-like behavior. In sharp contrast, Atp8al (-/-) mice displayed a preference for a stranger mouse over the novel object, which is characteristic of neurotypical mouse behavior. However, similar to the Atp8a1 + mice, the Atp8a1 (-/-) mice harbored fewer and weaker excitatory synapses in CM compared to wild-type controls, and displayed inhibition at 20-ms inter-stimulus interval in PPR. These findings suggest that both elevated and diminished levels of Atp8a1 during early development are detrimental to brain connectivity, but only elevated Atp8a1 is associated with aberrant social behavior. Mice with augmented levels of Atp8a1 may therefore serve as a potential model in autism research. (C) 2016 Elsevier B.V. All rights reserved.